When Rebecca Robinson showed up at the hospital expecting to receive her infusion of Doxil, a chemotherapy drug, last July, her doctors delivered the shocking news that they didn’t have any more of the drug.
Supplies of Doxil, a cornerstone for treating cancers known as sarcomas, had fallen short nationwide, along with methotrexate, a drug for treating childhood cancer, after one of the largest domestic suppliers of the drug shut down its plant over quality-control issues. What happened to Robinson, 37, as a result of the shortages is just one case study in how disruptive the shortfalls continue to be for hundreds, perhaps thousands of patients.
Robinson was diagnosed with angiosarcoma, a rare form of the cancer that often starts in the blood before spreading to other organs. Her cancer had infiltrated her liver, but the five rounds of Doxil she received before stores ran out had kept the growth in check. Her doctors were hoping to stall the cancer and make Robinson eligible for surgery to remove the biggest masses. And the strategy was working; she had not experienced too many side effects and felt strong enough during her chemo regimen to continue working full time as a historical interpreter in Massachusetts’ Old Sturbridge Village.
But with no Doxil left for her sixth session, Robinson’s doctor decided to put her on Taxol. The drug is also effective against angiosarcoma — but it wasn’t for Robinson. She not only had to give up a day of work a week for the treatments (instead of one day a month for Doxil therapy), but she also developed nausea, pain in her hands and feet and extreme fatigue. She lost her hair.
All of that would have been worth it if the drug had continued to shrink her cancer. But after a month, a CAT scan showed that her existing tumors had grown and that new ones had sprouted in both her liver and pelvis.
Robinson then moved onto doxorubicin, an older form of Doxil that isn’t as gentle on the body and often triggers nasty side effects. The drug left her nauseous and exhausted and forced her to come in for injections of a white-blood-cell booster the day after each infusion in order to keep her immune system running. But a scan several months later showed that the chemotherapy was at least keeping her tumors in check; they didn’t appear to be expanding or venturing out to seed new growths.
Because of her combined Doxil and doxorubicin sessions, however, Robinson has reached her lifetime limit for the toxic medications. Too much exposure to the drugs, while good for incapacitating tumors, can also damage the heart, so her doctor decided to stop her treatments before she started experiencing cardiac problems.
Now Robinson is on another drug called Nexovar, which gave her such a severe skin reaction that she had to stop using it for a month. The entire ordeal has left her too spent to work much anymore. “Lately I’ve been going in four to five hours a day and leaving when I get exhausted,” she says. “And how many days a week I work really depends on the week. This week I went in five days, but last week it was four days.”
And Robinson isn’t the only cancer patient who is anxious about what would happen if she can’t continue on her chemotherapy medication and possibly becomes too sick to go work or to school or is confined to a hospital bed, too weak to rise or visit with her family. “I tend not to be terribly volatile,” Robinson says of her reluctance to think about where she might be had she been able to continue her Doxil therapy. But, she says, “in my mind, there is no reason I should have to be on a version of a drug that makes me miserable when there’s another drug on which I was very comfortable. That just doesn’t make sense to me.”
It baffles her physician as well and has doctors increasingly worried. “The shortages clearly impact the way we care for patients,” says Dr. James Butrynski, Robinson’s cancer doctor at Dana Farber and an instructor of medicine at Harvard Medical School. “For the majority of patients we are treating with Doxil, we are achieving some clinical benefit, and for us to change treatment, that’s a challenge because we have a winning situation and when we change, there’s a risk that another medication won’t be as successful.”
The shortfalls have led to a number of changes in the way doctors and hospitals now manage cancer drugs. At Dana Farber, a member of the pharmacy staff is now dedicated full time to monitoring drug supply. When inventories start to drop, this staff member picks up the phone to call not just distributors and vendors but manufacturers themselves to glean as much information as she can about how serious the drop in supply is and how long it could last. That’s something that Sylvia Bartel, Dana Farber’s vice president of pharmacy, says the cancer center never had to worry about until recent years. The institute relied on a wholesaler who would simply take their orders and procure the drugs. “Now we are making contacts we never had to make before to ensure we have enough supply of drugs to treat our patients,” she says.
In fact, the American Society of Health-System Pharmacists reports that pharmacists now spend an average of eight to nine hours a week addressing drug shortages, compared with three hours a week in 2004. And doctors are increasingly spending more of their time drawing up alternative drug-treatment plans for their patients and managing side effects and monitoring effectiveness.
At the University of Virginia Children’s Hospital, doctors have started to pool patients to make the most efficient use of what little drugs they have. Because children use smaller doses than adults, more than one child can be treated with each vial of a chemotherapy drug like methotrexate.
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But that’s not an ideal solution. So the Food and Drug Administration (FDA) stepped in last month to address the shortfalls in both Doxil and methotrexate by calling in additional U.S. manufacturers and accepting shipments of one of the drugs from an overseas manufacturer. The action has averted the immediate threat for many patients, but doctors and patients still aren’t confident that another crisis won’t occur in a few months. “I know our institution has enough drug for patients now and for probably the next month to couple of months,” says Dr. Kimberly Dunsmore, chief of pediatric hematology oncology at University of Virginia Children’s Hospital. “But I don’t know what will happen after that. These drugs are the cornerstone of treatment for patients with osteogenic sarcoma and acute lymphoblastic leukemia … It’s frightening to think of putting these patients at risk by not being able to use these vitally important medicines. I’m very nervous about the next four, five and six months.”
Most doctors feel that the actions by the FDA are merely a stopgap, a temporary fix for a potentially explosive problem that won’t go away until changes are made to the way drugs are made, regulated, sold and distributed in this country.
President Obama’s October Executive Order could be a start. The order charges the FDA with requiring all manufacturers to inform the agency of any potential shortfalls they anticipate in their supply of any drug, whether due to manufacturing problems, plant closures, business decisions to discontinue drug production or problems in obtaining adequate raw materials. Currently, only manufacturers that are the sole maker of a drug are required to report to the FDA if they experience any changes in their production schedule.
The President also asked the FDA to boost its efforts to expedite drug approvals and overseas applications to ensure that enough manufacturers are supplying drugs. That’s already happening with methotrexate; the FDA accelerated review of a pending application by Illinois-based APP Pharmaceuticals to make the preservative-free injectable form of the drug. FDA Commissioner Margaret Hamburg has also exercised the agency’s authority to grant temporary approval for unapproved drugs, in this case for a form of Doxil called Lipodox, made by India-based Sun Pharma, to address the Doxil shortage.
But why did it take the agency nearly seven months to take these actions? Hamburg says the FDA needs more authority to enforce the requirement that drugmakers alert the FDA when they anticipate production problems. The President’s order is not enough. “Additional authority for the FDA to require early notification would clearly benefit our ability to rapidly mobilize and use tools we have available to us to help address existing shortages and prevent new shortages,” she says.
But already, as media reports of the cancer-drug shortages have emerged in recent months, Hamburg says manufacturers have been more forthcoming about potential supply issues. “The FDA was able to actively engage and prevent 195 shortages in 2011,” she says, with 99 of those due to early reporting by the companies affected. However, only an act of Congress can officially grant the FDA the authority to require such reporting, and a bill has been languishing in Washington since 2011.
While early notification to the FDA would help the agency better prepare for a potential drug shortage, such reporting is only one piece of an effective solution — it is reactive, not proactive. Currently, there is no single entity that keeps tabs on all potential contributors to a drug shortage. What the system needs is a clearinghouse of information that draw on what manufacturers know about pending production problems, what suppliers of the raw materials know about the availability of their ingredients and what the FDA is privy to regarding which companies are applying for approval for new drugs.
To that end, the Generic Pharmaceutical Association (GPhA) has submitted a proposal to the Department of Health and Human Services for an Accelerated Recovery Initiative, which would involve the entire drug manufacturing and supply chain. Its key feature: an independent third party that would serve as the liaison between generic drug makers and the FDA to coordinate and ensure an adequate supply of drugs. “The third party would collate information on inventories and inspections and drug supplies, and absorb it and regurgitate it back to the appropriate people,” says David Gaugh, senior vice president for regulatory sciences at GPhA.
Adds Ralph Neas, GPhA’s president and CEO: “If we have five or six manufacturers making a sterile injectable production, and say A and B are having problems. Then the third party would see what C, D and E could do to work out production issues.”
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By looping in the FDA, the independent party would also know if there is another company waiting for approval of the same drug that the agency could expedite.
Whether these measures will be enough and whether they will actually be implemented are two different issues. But for patients like Robinson, whatever the solution, it may be too late. Although her hospital now has enough Doxil to treat its patients, she can no longer take the drug for safety reasons. By taking the alternative drugs, she reached her lifetime limit of that class of medication. “I don’t have any confidence that the shortages are gone,” she says. “I expect it’s going to happen again, just because of the way it happened — there wasn’t any concern for patients. I felt like there was lots of concerns for the producers of medicines and for regulations, but there didn’t seem to be any concern at all for the patient.”